Exposure to maternal depression during pregnancy is common and associated with adverse medical and behavioral outcomes in infants. However, little is known about mechanisms underlying early adverse effects. This information is critical for early identification and intervention efforts with high-risk infants. In animal models, maternal prenatal stress results in long-term dysregulation ("programming") of the hypothalamic pituitary adrenocortical (HPA) stress response and neurobehavior. Prominent mechanisms underlying effects of prenatal stress in animals involve increases in maternal glucocorticoids and downregulation of placental 11[unreadable] hydroxysteroid dehydrogenase type 2 (11[unreadable] HSD 2), an enzyme that inactivates cortisol to cortisone. Our group has begun to translate this animal work to humans. We have shown effects of maternal depressive symptoms on fetal and neonatal stress response and neurobehavior. We have also shown that placental 11[unreadable] HSD 2 is downregulated by norepinephrine, which is, in turn, regulated by the placental norepinephrine transporter (NET). Critical next steps in our program of research and the field are to determine effects of major depressive disorder (MDD) rather than depressive symptoms on fetal/neonatal stress response and neurobehavior, and to elucidate pathways linking prenatal MOD to fetal/neonatal neurobehavioral dysregulation. Thus, our aims are: 1) to characterize effects of pregnancy MDD on fetal and neonatal stress response and neurobehavior, 2) to test the hypothesis that maternal MDD influences fetal/neonatal stress response via alterations in maternal cortisol, and downregulation of placental NET and 11[unreadable] HSD 2. In response to reviewer concerns, we added an exploratory aim to examine effects of comorbid MDD + anxiety disorders relative to MDD-only on fetal/neonatal neurobehavior and maternal-placental HPA regulation. This revised application proposes an intensive, longitudinal investigation of maternal MDD, maternal-placental neuroendocrine dysregulation, and fetal/neonatal stress response and neurobehavior. Three groups of mothers and offspring will be identified: a) mothers with MDD during pregnancy (including MDD- only and MDD + anxiety disorder), b) mothers with a history of MDD who remain euthymic during pregnancy, and c) mothers with no history of or current psychiatric disorder (controls). Neonatal assessment will involve cortisol and behavioral response to a neurobehavioral examination at 1-2 and 30 days;fetal assessment will include heart rate and behavioral response to vibroacoustic stimulus. Measures of maternal-placental neuroendocrine regulation will include maternal circadian cortisol, and placental NET and 11[unreadable] HSD 2 gene expression. Results may elucidate early markers of risk and help to delineate early pathways to later behavioral dysregulation. Early identification of high-risk fetuses and infants may also lead to education for parents to improve interactions with stressed newborns, and, potentially, novel therapeutic targets to protect fetuses from consequences of maternal depression.